Opthea Ltd — Investor Presentation 2017

Apr 2, 2017

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OPT-302: Phase 1/2A wet AMD Trial Update Corporate Update , April 3 2017 Megan Baldwin, CEO & Managing Director

Disclaimer

Investment in Opthea Limited (‘Opthea’) is subject to investment risk, including possible loss of income and capital invested. Neither Opthea nor any subsidiary of Opthea guarantees any particular rate of return or performance, nor do they guarantee the repayment of capital.

This presentation is not an offer or invitation for subscription or purchase of or a recommendation of securities. It does not take into account the investment objectives, financial situation and particular needs of the investor. Before making any investment in Opthea, the investor or prospective investor should consider whether such an investment is appropriate to their particular investment needs, objectives and financial circumstances and consult an investment advisor if necessary.

This presentation may contain forward-looking statements regarding the potential of the Company’s projects and interests and the development and therapeutic potential of the Company’s research and development. Any statement describing a goal, expectation, intention or belief of the company is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercialising drugs that are safe and effective for use as human therapeutics and the financing of such activities. There is no guarantee that the Company’s research and development projects and interests (where applicable) will receive regulatory approvals or prove to be commercially successful in the future. Actual results of further research could differ from those projected or detailed in this presentation. As a result, you are cautioned not to rely on forward-looking statements. Consideration should be given to these and other risks concerning research and development programs referred to in this presentation.

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Corporate Summary

• OPT-302 is in development for the treatment of wet Age-related Macular Degeneration (‘wet AMD’), a progressive eye disease that is the leading cause of blindness in people over the age of 50 years

• OPT-302 blocks VEGF-C and VEGF-D that cause vessels to grow and leak and are hallmarks of wet AMD disease progression

• Approved therapies for wet AMD block VEGF-A and include blockbuster drugs Lucentis® and Eylea®. In 2016, Lucentis® and Eylea® generated revenues > USD 8.5 billion

• Existing therapies targeting VEGF-A are sub-optimally clinically effective in the majority of patients – major unmet medical need

Strategy:

• To develop OPT-302 for use in combination with existing VEGF-A inhibitors for the treatment of eye diseases

• Achieves more complete blockade of the VEGF pathway involved in disease progression

• Blocks mechanisms of clinical ‘resistance’ to existing therapies

Clinical Development:

• Phase 1/2A wet AMD clinical trial run under FDA approved IND at 14 US clinical sites

• Plans to expand OPT-302 clinical development program with a larger Phase 2B wet AMD clinical trial and Phase 2A clinical trials for diabetic macular edema (‘DME’) and in prior-treated wet AMD patients

• Phase 2B and Phase 2A DME and prior-treated patient trials to initiate in 2H 2017

• Diversifies clinical development strategy in multiple eye diseases

• Multiple upcoming clinical development milestones

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OPT-302 Phase 1/2A

ClinTrials.gov ID#: NCT02543229

Dose-escalation & dose-expansion of repeated IVT injections

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Phase 1: Dose-escalation Phase 2A: Dose-expansion
(Open-label) (Randomised)
OPT-302 (2.0 mg) OPT-302 (2.0 mg)
Monotherapy Monotherapy
IVT Q4W x 3, n=5 IVT Q4W x 3, n=8 pts
Cohort 4
OPT-302 (2.0 mg) OPT-302 (2.0 mg)
+ Lucentis® (0.5 mg) + Lucentis® (0.5 mg)
IVT Q4W x 3, n=5 IVT Q4W x 3, n=23 pts
Cohort 3
OPT-302 (1.0 mg)
+ Lucentis® (0.5 mg)
IVT Q4W x 3, n=5
Cohort 2
OPT-302 (0.3 mg)
+ Lucentis® (0.5 mg)
IVT Q4W x 3, n=5
Cohort 1 Access to rescue anti-VEGF-A Tx
28 Day DLT window Follow-up to week 12
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*Access to rescue anti-VEGF-A Tx

• Each patient dosed on a monthly basis for 3 months

• Primary data analysis at week 12

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OPT-302 Phase 1/2A: Patient Cohorts

Phase 1/2A

• 51 patients, 32 (63%) females, 19 (37%) males, mean age 77 years

• 37 /51 (73%) occult, 12/51 (23%) min classic, 2/51 (4%) predominantly classic

• Mean min classic component 5.9%

• 49% treatment-naïve

• 51% difficult to treat patients sub-responsive to anti-VEGF-A therapy

• Mean number prior anti-VEGF-A injections: 17

Cohort	Treatment	# Naïve Pts	# Prior Treated Pts
1	OPT-302(0.3 mg)+ Lucentis®(0.5 mg)	2	3
2	OPT-302(1.0 mg)+ Lucentis® (0.5 mg)	0	5
3 & 5	OPT-302(2.0 mg)+ Lucentis® (0.5 mg)	16	12a
	Total Combination Tx	18	20
4 & 6	OPT-302(2.0 mg)	7b	6

• a. One patient with metastatic ovarian cancer/pulmonary embolism died prior to the week 12 (day 69) visit due to intercurrent illness unrelated to study drugs

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• b. One patient with a myocardial infarction died prior to the week 12 (day 77) visit (unrelated to study drugs)

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Phase 1/2A Visual Acuity Outcomes

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In MARINA trial (Phase 3 registrational): ~6 letters gain in vision compared to baseline at Week 12 in patients with minimally classic/occult wet AMD lesions treated with Lucentis® (ranibizumab)

Opthea’s Phase 1/2A trial recruited patients with wet AMD lesion types similar to those patients recruited into the MARINA study

Wk12

Treatment	OPT-302: Phase 1/2A
Overall % Patients Gained/Maintained Vision to Wk 12	44/49(90%)
% Patients Non-Rescued in OPT-302 Monotherapy	54%(n=7/13)
Mean Change Visual Acuity at Wk 12 (letters)
Combo OPT-302 + Lucentis® inNaïvepts	+10.8(n=18)
Combo OPT-302 + Lucentis® inPrior Txpts	+4.9(n=19)
Combo OPT-302 + Lucentis® in bothNaïve & Prior Txpts	+7.8(n=37)
OPT-302Monotherapyin Non-Rescue pts	+5.6(n=7)

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* Rosenfeld et al., NEJM, 355;14, pp 1419-1431, 2006. In MARINA, occult lesions (62% pts), min.classic (38% pts)

Phase 1/2A: Patients Gaining or Maintaining Vision @ Wk12

• 51 patients enrolled

• 49 patients evaluable at the week 12 endpoint

Cohort	Treatment	# patients	# pts Gained or Maintained	# pts Gained	# pts Maintained	# pts lost less than 5 letters	# pts lost b/w >5 = <10 letters
1 -6	ALL: OPT-302 (0.3/1.0/2.0 mg) +/- Lucentis®	49	44 (90%)	37 (76%)	7 (14%)	3	2
1,3,5	Naïve: OPT-302 (0.3/2.0 mg) + Lucentis®	18	16 (89%)	14 (78%)	2 (11%)	1(-3 letters)	1(-8 letters)*
1-3,5	Prior Tx: OPT-302 (0.3/2.0 mg) + Lucentis®	19	19 (100%)	16 (84%)	3 (16%)	0	0
4,6	Monotherapy: All	12	9 (75%)	7 (58%)	2 (16%)	2	1
	Monotherapy: Non-Rescue	7	7	5	2	0	0
	Monotherapy: Rescue	5	2	2	0	2 (-3,-2 letters)	1 (-5 letters)

• 44/49 (90%) patients enrolled in the study gained or maintained vision at week 12

• 5/49 (10%)* patients lost between -2 and -8 letters

• All of the patients that had a decrease in vision received Lucentis® therapy

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* In the MARINA study, 13% of patients that received Lucentis® therapy had lost ≥6 letters at week 12 (Hariprasad et al., J Ophthal., 2012)

Phase 1/2A: Naïve Patients OPT-302 (0.3 & 2mg) + Lucentis[®] (0.5mg)

Mean Change in Visual Acuity from Baseline (letters)

Mean Sub-Retinal Fluid (SRF) (uM)

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Mean Central Subfield Thickness (CST) (uM)

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Naïve patients:

• Mean gain in visual acuity at week 12 from baseline was +10.8 letters

• In the MARINA[*] trial, ~+6 letters gain in vision compared to baseline at Week 12 in patients treated with monthly Lucentis®

• CST was reduced by 119 uM to 283 uM , approaching normal retinal thickness

• SRF reduced by 83% by Week 12

• At week 12, 72% (13/18) patients had complete (100%) resolution of SRF

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Number of Patients: 18 Mean Baseline VA = 56.5 Letters (MARINA: Mean Baseline VA = 53.7 letters)

• Rosenfeld et al., NEJM, 355;14, pp 1419-1431, 2006

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Phase 1/2A: Naïve Patients OPT-302 (0.3 & 2mg) + Lucentis[®] (0.5mg)

Improved Visual Outcome through week 12

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≥ 2 line gain ≥ 3 line gain
60 35
30
50
25
40
20
30
15
20
10
10
5
0 0
Week 4 Week 8 Week 12 Week 4 Week 8 Week 12 Week 12
OPT-302 + Lucentis® OPT-302 + Lucentis® Lucentis®
MARINA trial
% Patients % Patients
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*Mean ranibizumab data (0.3 & 0.5 mg) from MARINA trial: Hariprasad et al J Opht 2012 p1-8; Rosenfeld et al NEJM 2006, Vol 355, No. 14, pp. 1419-1431

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Number of Patients: 18 10 Mean Baseline VA = 56.5 Letters MARINA: Mean Baseline VA = 53.7 letters

Prior-Treated Patients: Visual Acuity

• Majority of vision gain in Lucentis® treated patients occurs within 3 months

• Plateau “ceiling effect” of response with no other treatment options

• Difficult to treat patient population, very large market opportunity

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Plateau of Response after 3 mos
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MARINA Phase 3 in wet AMD. Rosenfeld et al., NEJM, 355;14, pp 1419-1431, 2006

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Phase 1/2A: Prior-Treated Patients

OPT-302 (0.3, 1 & 2mg) + Lucentis[®] (0.5mg)

Mean Change in Visual Acuity from Baseline (letters)

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Mean Central Subfield Thickness (CST) (uM)

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Mean Sub-Retinal Fluid (SRF) (uM)

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Prior-Treated patients:

• Mean number prior anti-VEGF-A injections per patient: 17

• Mean gain in visual acuity at week 12 from baseline was +4.9 letters

• Mean reductions in CST and SRF at week 12 of 54 uM and 62 uM (51%) respectively from baseline

• 3/19 (16%) patients had complete (100%) resolution of SRF

• 9/19 (47%) had > 50% resolution of SRF at week 12 compared to baseline

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Number of Patients: 20 pts (BL, Wk 4, Wk 8), 19 pts (Wk 12)

OPT-302 Monotherapy

• OPT-302 monotherapy included to identify clinical activity without a background standard of care

• Natural history of wet AMD: without treatment, often chronic, rapid decline in visual acuity and increase in retinal fluid

• a-VEGF-A rescue therapy offered to patients at physician discretion or if patient met criteria of progression according to defined criteria

Treatment	# patients	# Naïve pts	# Prior Tx pts
OPT-302, 2 mg	13a	7 (54%)	6 (46%)
No rescue	7 (54%)	4 (57%)	3 (50%)
Rescue	6 (46%)	3 (43%)	3 (50%)

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a One naïve patient in the monotherapy cohort with myocardial infarction died (on day 77) prior to the week 12 visit (unrelated to study drugs)

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Phase 1/2A: Monotherapy Patients OPT-302 (2mg) (Naïve & Prior-Treated)

Mean Change in Visual Acuity in NonRescue Patients at Each Time Point

Visual Acuity in Non-Rescue Patients at Each Time Point

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Naïve Patients Prior Tx Patients
2 5 2 5
2 0 2 0
1 5 1 5
1 0 1 0
5 5
0 0
-5 MARINA -5 MARINA
Sham injection Sham injection
at Wk12 at Wk12
-1 0 -1 0
w e e k 4 w e e k 8w e e k 1 2 s h a m w e e k 4 w e e k 8w e e k 1 2 s h a m
V isu al A c u ity V isu al A c u ity
(M e a n C h a n g e fro m B a s e lin e ) (M e a n C h a n g e fro m B a s e lin e )
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One naïve patient in the monotherapy cohort with myocardial infarction died (on day 77) prior to the week 12 visit (unrelated to study drugs)

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* Rosenfeld et al., NEJM, 355;14, pp 1419-1431, 2006

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Phase 1/2A: Monotherapy Patients OPT-302 (2mg) (Naïve & Prior-Treated)

• 7/13 (54%) patients did not require ‘rescue’ therapy

Visual Acuity in Patients who were

not rescued by Week 12

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5.6
6 (7/12)
4.3
3.9
(7/13)
(7/13)
4
2
0
B a s e lin e W e e k 4 W e e k 8 W ee k 12
V is u a l A c u ity
(M e a n C h a n g e fro m B a s e lin e )
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Sub-Retinal Fluid in Patients who

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were not rescued by Week 12
2 0 0 192 183
(-9)
137
1 5 0 (-56)
101
(-91)
1 0 0
5 0
0
B a s e lin e W e e k 4 W e e k 8 W ee k 12
S R F (u M )
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Monotherapy Patients, at week 12:

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Central Sub-Field Thickness in Patients
who were not rescued by Week 12
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4 0 0 390
391 (-1)
373 376
3 8 0 (-18) (-15)
3 6 0
3 4 0
C S T (u M )
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• 7/13 (54%) patients did not require ‘rescue’ therapy

• Patients that did not require rescue therapy had:

• a mean visual acuity gain of 5.6 letters from baseline (range 0 to 18 letters)

• a mean decrease in CST of -15 uM (baseline CST non-rescue pts: 390 uM) and

• a 91 uM reduction in SRF

• 6/13 (46%) patients were rescued with a-VEGF-A therapy

• Despite rescue with Lucentis®, 3/5 evaluable patients at week 12 had a decrease in vision compared to baseline (-2, -3, -5 letters)

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B a s e lin e

W e e k 4

W e e k 8 W ee k 12

Phase 1/2A Safety Summary

• OPT-302  Lucentis® administered by repeat IVT injection (Baseline, Week 4, Week 8)

• No missed doses, safety experience with ~150 intravitreal (ocular) injections of OPT-302

• OPT-302 at ocular doses up to 2 mg  Lucentis[®] (0.5 mg):

• No dose limiting toxicities (MTD was not reached)

• No drug-related serious adverse events or systemic adverse events

• 2/51 patients (4%) had ocular adverse events related to OPT-302 study drug

• Adverse events were Grade 1/Mild in the low and mid-dose combination groups

• Majority of ocular emergent adverse events primarily related to IVT injection procedure

• (31/51 patients; 59%); majority were Grade 1/Mild or Grade 2/moderate and manageable

• No signs of infection (endophthalmitis)

• There were 2 patient deaths due to underlying disease, not considered related to study treatment

• One patient at study day 69 with metastatic ovarian cancer & pulmonary embolism

• One patient at study day 77 with myocardial infarction

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OPT-302 Phase 1/2A: Key Take-Aways

• OPT-302 met primary safety objective of Phase 1/2A study (well tolerated)

• Evidence of clinical activity of OPT-302 (anti-VEGF-C/D) in patients including heavily pre-treated patients (51%) and a high proportion of occult (73%) wet AMD lesions:

• Naïve Patients :

  • Results suggest OPT-302 + Lucentis® may lead to improved outcomes over Lucentis® alone, suggesting additional benefit with more complete suppression of VEGF-A + VEGF-C/D

• Prior Treated Patients:

  • Evidence of improved clinical outcomes, including gain in visual acuity and reduction in CST and SRF, despite long-term prior treatment with anti-VEGF-A

• Monotherapy Patients:

  • Evidence of clinical activity and visual acuity gains without background standard of care

• A consistency of responses in patients:

• With different treatment histories

• Across various secondary outcome measures (VA, OCT)

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OPT-302 Proposed Phase 2B in Wet AMD

Combination OPT-302 + Lucentis® vs Lucentis®

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Wet AMD
Naïve Pts
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OPT-302 (Dose 1) + Lucentis® (0.5 mg)
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Primary
Endpoint:
Mean Change in
Visual Acuity from
Baseline at Week 24
Secondary
Endpoints:
Retinal Thickness
(SD-OCT, wk 12, 24)
Area of CNV leakage
(FA, wk 12 & 24)
% pts ≥3 line gain in VA
Ocular & Systemic AEs
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OPT-302 (Dose 2) + Lucentis® (0.5 mg)
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Lucentis® (0.5 mg)
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All treatment arms : IVT dosing at every 4 weeks (x 6)

• Phase 2b Prospective, randomized, controlled trial

• 3 arms (randomized 1:1:1)

• Primary Analysis at 6 months

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OPT-302 Proposed Phase 2A in Diabetic Macular Edema

Combination OPT-302 + Lucentis® vs Lucentis®

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Dose-escalation Phase 2A: Randomized (1:1)
Dose-expansion
Lucentis® (0.3 mg)
Std.of Care
IVT Q4W x 3,~n=40 pts
OPT-302 (TBD)
+ Lucentis® (0.3 mg)
IVT Q4W x 3, ~n=40 pts
OPT-302 (2.0 mg)
+ Lucentis® (0.3 mg)
IVT Q4W x 3, n=5
OPT-302 (0.3 mg) Cohort 2
+ LucentisOPT-302 (1.0 mg)® (0.3 mg)
+ Lucentis IVT Q4W x 3, n=5 ® (0.3 mg)
IVT Q4W x 3
Cohort 1
ow
d
Follow-up to week 12
Follow-up to week 12
28 Day DLT win Long term follow-up at Week 24
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Primary endpoint:

• Dose-escalation: Systemic & Ocular AEs;

• Phase 2A: Mean change from baseline in CST at week 12 (SD-OCT)

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Opthea – Developing OPT-302 for Eye Diseases

• OPT-302 has broad development potential in a range of eye diseases, including wet AMD and DME

• Targets validated pathway involved in wet AMD progression and mechanism of escape from existing therapies that is differentiated to a-VEGF-A therapies

• Large unmet medical need for wet AMD, current treatments only target VEGF-A

• Wet AMD landscape of products in development includes only a limited number of novel combination therapies that may address the sub-optimal clinical responses that many patients experience on anti-VEGF-A therapies

• OPT-302 met primary safety objective of Phase 1/2A study (well tolerated) and demonstrated evidence of clinical activity in a 51 patient Phase 1/2A clinical trial that enrolled naïve and prior treated patients administered OPT-302 monotherapy and OPT-302 in combination with Lucentis®

• Opthea plans to expand its clinical development program by conducting:

• A randomised Phase 2B clinical trial of OPT-302 + Lucentis® compared to Lucentis® alone in ~350 wet AMD patients

• A randomised Phase 2A clinical trial of OPT-302 + Lucentis® compared to Lucentis® alone in ~90 DME patients

• A Phase 2A clinical trial of OPT-302 + Lucentis® compared to Lucentis® alone in prior-treated wet AMD patients

• The expanded program establishes and diversifies a robust OPT-302 clinical development strategy, whilst increasing the potential value accretion points for the program

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Suite 0403, Level 4, 650 Chapel Street, South Yarra 3141 Victoria Australia T +61 (3) 9826 0399 E megan.baldwin@opthea.com

www.opthea.com